Hydrazones of 5-nitro-2-furaldehyde



United States Patent HYDRAZONES GE S-NITRO-Z-FURALDEHYDE Wilfred Herbert Hook, Broolrlands, Sale, and William Hoyle, Bramhall, England, assigriors to Geigy Chemical Corporation, Ardsley, N.Y., a corporation of Delaware No Drawing. Filed Nov. 26, 1962, Ser. No. 240,163 Claims priority, application Great Britain Nov. 30, 1961 15 Claims. (Cl. 26024tl) The present invention relates to new hydrazoues of nitro-Z-furaldehyde which possess useful pharmacological, in particular anti-microbial properties as well as to processes for producing said hydrazones.

It has been found that S-nitro-Z-furaldehyde-N- triazinyl-hydrazones of the formula wherein R and R independently of each other are hydrogen, alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl or aralkyl radicals, the two latter being substituted, if desired, e.g. by halogen atoms, trifluoromethyl, lower alkyl and/or lower alkoxy groups, R and R independently of each other are hydrogen, lower alkyl or lower hydroxyalkyl radicals and one or two pairs of alkyl radicals R and R and/ or R and R, can be linked direct or by Way of an oxygen atom, as Well as their salts with inorganic and organic acids, exhibit outstanding antimicrobial activities, in particular against bacteria such as staphylococcus, streptococcus and tubercle bacilli, and against protozoa such as trichomonas foetus. Further they possess also antifungal, anthelmintic and coccidiostatic properties. In particular, the following compounds of Formula I inhibit the growth of different strains, including drug-resistant strains of tubercle bacilli in Youmans serum-agar (Am. Rev. Tbc, 55, 530 (1947)) in a concentration of 1 ppm. and lower:

5-nitro-2-furaldehyde-N- [4'-ethylamino-6'-diethylamino-1',3 ,5 -triazinyl- (2') J-hydrazone,

5 -nitro-furaldehyde-N'- [4'-isopropylamino-6-diethylamino- 1 ,3 ,5 -triazinyl- (2) ]-hydrazone,

5-nitro-furaldehyde-N- [4',6-bis- (ethylamino l ,3 ,5

triazinyl- (2' -hydr azone,

5-nitro-furaldehyde-N- [4,6'-bis- (isopropylamino 1,3 ,5 -triazinyl- (2 -hydrazone,

5-nitro-furaldehyde-N- [4'-rnethylamino-6'-isopropylamino-1',3 ,5 -triazinyl- (2 1 -hydrazone,

5-nitro-furaldehyde-N- [4-ethylamino-6-isopropylamino-1,3 ',5'-triazinyl- (2) ]-hydrazone,

5 -nitro-furaldehyde-N- 4'-allylamino-6-isopropylamino-1,3',5-triazinyl- (2 -hydrazone,

5-nitro-furaldehyde-N- [4-rnethylamino-6'-sec. butylamino-1,3 ,5 '-triazinyl- (2') ]-hydrazone,

5-nitro-furaldehyde-N- [4-ethylamino-6- ('ynethoxypropylamino -l ,3 ,5'-triazinyl- (2) ]-hydrazone sulphate and 5-nitro-furaldehyde-N- [4-amino-6-isopropylamino- 1,3 ,5 '-triazinyl- (2) 1-hydrazone.

The growth of trichomonas foetus in trichomonas medium according to G. Johnson and R. E. T russel, Proc. Soc. Exp. Biol. Med. 54, 245 (1943) is inhibited, for instance, by 5-nitro-2-furaldehyde-N'-[4,6'-bis-(isopropylamino 1 ,3,5 '-triazinyl- (2) ]-hydrazone and S-nitrofuraldehyde N [4,6'-bis-(tert. butylamino-1,3,5-triazinyl-(2)]-hydraz0ne in a concentration of ppm.

"ice

In the compounds of the Formula I, R and R are hydrogen, alkyl having at most 8 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, tert, butyl, n-amyl, isoamyl, n-hexyl, n-octyl, lmethyl-heptyl; alkenyl with 3 to 4 carbon atoms such as allyl, crotyl, methallyl; hydroxy(lower)alkyl such as ,B-hydroxy-ethyl, ,B-hydroxypropyl, -hydroxypropyl; lower alkoxy (lower) alkyl such as fi-methoxyethyl, fi-ethoxyethyl, fl-n-butoxyethyl, 'y-methoxypropyl, y-isopropoxypropyl; cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; phenyl; halogenophenyl such as fluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl; trifluoromethylphenyi; lower alkylphenyl such as methylphenyl, dimethylphenyl; lower alkoxyphenyl such as methoxyphenyl, ethoxyphenyl, isopropoxyphenyl; phenyl (lower)alkyl such as benzyl, ,B-phenylethyl; halogenophenyl(lower)alkyl such as chlorobenzyl; (lower)alkylphenyl(lower)alkyl such as p isopropylbenzyl; as well as (lower alkoxy) phenyl(lower)alkyl such as 3, 4-dimethoxybenzyl. Radicals R and R are hydrogen, alkyl having at most 8 carbon atoms as defined under R and R and hydroxy (lower) alkyl as defined under R and R The group NR R and independently thereof the group NR R, can represent heterocyclic 5-, 6- or 7-rings such as l-pyrrolidinyl, piperidino, morpholino and hexamethyleneimino.

The term lower as used in conjunction with alkyl and alkoxy means that the respective radical contains not more than 4, and preferably up to 3 carbon atoms.

Preferred compounds are compounds of the Formula I wherein R and R have the meanings given above and R and R are taken from methyl, ethyl, propyl, [ihydroxyethyl and, especially, hydrogen.

The new compounds of Formula I defined above are prepared by reacting 5-nitro-2-furaldehyde or a functional derivative thereof with a hydrazino-triazine of the formula lila (11) wherein R R R and R have the meanings given above, or with a salt thereof. The reaction is carried out, e.g. by heating the reaction components in a suitable organic solvent or diluent such as ethanol, isopropanol, butano-l, benzene or toluene.

Instead of the free aldehyde, a functional derivative thereof such as its diacetate, for example, is used and the reaction is promoted, if necessary, e.g. by the addition of a small amount of sulphuric acid.

According to a further process, new hydrazones of Formula I are prepared by reacting S-nitro-Z-furaldehydehydrazone with cyanuric chloride or cyanuric bromide in the presence of an acid binding agent, and further reacting the resulting novel product of formula Hal l OzN- C H=NNH N O N I Hal (III) wherein Hal is chlorine or bromine, with equimolar amounts of a compound of the formula R2 (IV) and of a compound of the formula wherein R R R and R have the meanings given above, optionally in the presence of an acid binding agent. Compounds of the Formula IV and V can be different or identical; in the latter case the procedure is reduced to the steps of the formation of the compound of Formula III and the reaction thereof with twice the equimolar amount of a compound of Formula IV. The first reaction step is performed, for instance, in dioxane by using sodium bicarbonate or another alkali carbonate as acid binding agent. Dimethyl sulphoxide, for instance, is suitable as solvent for the reaction of a compound of the Formula III with an amine of the Formula IV wherein an excess of the amine to be reacted can, if desired, serve as acid binding agent, particularly when introducing two similar amino groups in the same step.

A modification of the above process consists in reacting, in the presence of an acid binding agent, 5-nitro-2- furaldehyde-hydrazone with a compound of the formula wherein R R and Hal have the meanings given above, and further reacting the resulting novel product which corresponds to the formula R1 I i-R2 CH=N NH N 0 Hal (VII) with a compound of the Formula V defined above.

Finally, compounds of Formula I are obtained by nitrating a compound of the formula wherein R R R and R have the meanings given above, with a mixture of concentrated nitric acid, acetic acid and acetic anhydride. Preferably the action is performed in the absence of water, e.g. by slowly adding a mixture of concentrated nitric acid, acetic acid and acetic anhydride to a suspension or solution of a compound of Formula VIII in acetic acid-acetic anhydride mixture while maintaining the temperature near C.

The compounds of the general Formula I obtained through any of the above mentioned processes are converted, if desired, into their salts with inorganic or organic acids. The following inorganic or organic acids are suitable for this purpose, e.g.: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane disulphonic acid, trichloroacetic acid, oxalic acid, succinic acid, maleic acid, fumari acid, malic acid, tartaric acid, citric acid, and mandelic acid.

The new hydrazones of the general Formula I can be used, according to their antimicrobial and further biological properties, particularly as single or additional active substances of antibacterial, antimycotic, anthelmintic and coccidiostatic agents, in concentrated or ready-for-use form for external as well as internal use in human and veterinary medicine. Furthermore, they can be added,

Example 1 A mixture of 11.2 g. of 2-hydrazino-4,6-bis-(methylamino)-1,3,5-triazine, ml. of ethanol and 14.1 g. of 5-nitro-2-furaldehyde is boiled under reflux for 2 /2 hours. The brown product is removed from the cooled liquor and recrystallised from methoxyethanol. After drying in vauco at 100110 the 5-nitro-2-furaldehyde-N'-[4',6'- bis-(methylamino)-l',3,5'-;triazinyl-(2)] -hydrazone so obtained melts at 252 with decomposition.

The 2-hydrazino-4,6-bis-(methylamino)-l,3,5 triazine may be prepared as follows:

A mixture of 17.4 g. of 2-chloro-4,6-bis-(methylamino)- 1,3,5-triazine, 237 ml. of ethanol and 15 g. of 100% hydrazine hydrate is boiled under reflux for 4 /2 hours. The reaction mixture is concentrated by distillation of 118 ml. of ethanol. To the residue ml. of water are added. The product after washing with water is recrystallised from water to give pure 2-hydrazino-4,6-bis- (methylamino)-1,3,5-triazine melting at 234-6 with decomposition.

Similarly can be prepared 5-nitro-2-furaldehyde-N'- [4',6'-bis(anilino)-1',3',5' triazinyl (2')] hydrazone melting at 255-258" with decomposition, and 5-nitro-2- furaldehyde-N' [4',6'-bis-(benzylamino)-l,3,5 triazinyl-(2)]-hydrazone melting at 203-204".

Example 2 A mixture of 15 g. of 2-hydrazino-4,6-bis-(ethylamino)- 1,3,5-triazine and 10.8 g. of S-nitrQ-Z-furaldehyde is boiled under reflux with 396 ml. of benzene. The reaction solution is boiled under reflux for one hour and then cooled. The 5-nitro-2-furaldehyde-N'-[4,6-bis-(ethylamino)-1',3',5-triazinyl-(2') J-hydrazone which separates is collected by filtration and washed with hot benzene. Recrystallisation of this product from ethanol gives orange red crystals melting at 220221 with decomposition. This compound can easily be converted e.g. into the following salts: hydrochloride, decomposes at 270300, ethane disulphonate, decomposes at 300-320, p-toluene sulphonate, decomposes at 250260, trichloroacetate, decomposes at 280-290", oxalate, melting at 213 with decomposition, and tartrate, melting at 216-217 with decomposition.

The 2 hydrazino-4,6-bis-(ethylamino)-1,3,5-triazine may be prepared as follows:

A mixture of 10.9 g. of 2-chloro-4,6-bis-(ethylamino)- 1,3,5-triazine, 7.5 g. of 100% hydrazine hydrate and 118 ml. of ethyl alcohol is boiled under reflux for 1% hours. The solution is concentrated by distillation of 79 ml. of ethyl alcohol. To the cooled residue 50 ml. of water are added, and the crystalline product is collected by filtration. The product after washing with water is recrystallised from benzene to give pure 2-hydrazino-4,6-bis-(ethylamino)-1,3,5-triazine melting at 1375-1385".

Similarly can be prepared 5-nitro-2-furaldehyde-N'-[4- methylamino 6-isopropylamino-1,3,5-triazinyl-(2)]- hydrazone melting at 203205.

Example 3 A mixture of 4.9 g. of S-nitro-Z-furaldehyde diacetate and 3.9 g. of 2-hydrazino-4,6-bis-(dimethylamino)-1,3,5- triazine in 78.9 ml. of absolute ethanol is boiled under reflux for hour. On cooling yellow crystals of 5-nitro- 2 furaldehyde-N-[4,6'-bis-(dimethylamino)-l,3',5'-triazinyl-(2')]-hydrazone are deposited. The compound is recrystallised from ethanol to give crystals melting at 201-202".

The 2-hydrazino-4,6-bis-(dimethylamino)-l,3,5-triazine may be prepared as follows:

A mixture of 20.2 g. of 2-chloro-4,6-bis-(dimethylamino)-1,3,5-ttriazine and 142 ml. of ethanol is boiled under reflux for 2 hours with 15 parts of 100% hydrazine hydrate. The solution is concentrated by distillation and 103 ml. of ethanol are collected. The residue is cooled and 50 ml. of water are added. The crystalline product is collected by filtration and well washed with water until the wash liquid contains no chloride ions. After drying, the 2-hydrazino-4,6-bis-(dimethylamino)-1,3,5-triazine is recrystallised from benzene to give colourless crystals melting at 147-149".

Example 4 A mixture of 5.6 g. of 2-hydrazino-4,6-bis-(morpholino)-1,3,5-triazine, 3.3 g. of S-nitrQ-Z-furaldehyde diacetate, and 0.5 g. of concentrated sulphuric acid in 59 ml. of ethanol, is boiled under reflux. After /2 hour the mixture is cooled and the yellow product collected on a filter. After recrystallisation from ethanol this product yields S-nitro-Zduraldehyde-N [4,6-bis- (morpholino) l,3,5-triazinyl-(2)]-hydrazone which melts at 262 264 with decomposition, and contains ethyl alcohol of crystallisation.

The 2 hydrazine-4,6-bis-(morpholino)-1,3,5-triazine may be prepared as follows:

A mixture of 8.6 g. of 2-chloro-4,6-bis-(morpholino)- 1,3,5-triazine, 99 ml. of ethanol and 4.5 g. of 100% hydrazine hydrate is boiled under reflux for 1 /2 hours. The solution is concentrated by distillation and 40 parts of ethanol are removed. To the cooled residue 50 parts of water are added. The product after washing with water is recrystallised from benzene to give pure 2-hydrazino 4,6-bis-(morpholino)-1,3,5-triazine melting at 189-191".

Example 5 A mixture of 2.4 g. of 2-hydrazino-4-isopropylamino-6- diethylamino-l,3,5-triazine, 24 ml. of ethanol and 2.1 g. of 5-nitro-2-furaldehyde is boiled under reflux for one hour. The solution is then cooled in ice and the yellow solid product is collected. Afiter recrystallisation from a mixture of benzene and petroleum ether, there is obtained S-nitro-2-furaldehyde-N-[4-isopropylamino-6-diethylamino-1,3,5-triazinyl-(2)]-hydrazone which melts at 172l74.

The Z-hydrazino-4-isopropylamino-6-diethylamino-1,3, S-triazine may be prepared as follows:

A mixture of 4.9 g. of 2-chlor-4isopropylamino-6-diethylarnino-1,3,5-triazine, 32 ml. of ethanol and 3 g. of 100% hydrazine hydrate is boiled under reflux for 2 hours. The solution is concentrated by distillation and 16 ml. of ethanol are removed. To the cooled residue 40 ml. of Water are added. The product after washing with water is recrystallised from petroleum ether to give pure 2-hydrazino 4-isopropylarnino-6-diethylamino-1,3,5-triazine melting at 100-102.

Similarly can be prepared:

5 nitro 2 furaldehyde N [4 ethylarnino 6- diethylamino-l,3,5-triazinyl-(2)]-hydrazone melting at 185l87, 5 nitro 2 furaldehyde N [4' methyl amino 6 diethylamino 1,3,5 triazinyl (2)] hydrazone melting at 220-221 with decomposition;

5 nitro 2 furaldehyde N [4 (2" hydroxyethylamino) 6 propylamino l,3,5 triazinyl (2)]- hydrazone melting at 152-154;

5 nitro furaldehyde N [4 amino 6 diethylamino 1,3,5 triazinyl (2)] hydrazone, melting at 254 (decomposition);

5 nitro furaldehyde N [4 amino 6 isopropylamino l,3,5 triazinyl (2)] hydrazone, melting at 237-239 (decomposition);

5 nitro furaldehyde N [4 methylamino 6- ethylamino l,3,5 triazinyl (2)] hydrazone, melting at 234237 (decomposition);

5 nitro furaldehyde N [4 methylamino 6- tert. butylamino 1,3,5 triazinyl (2)] hydrazone, melting at 219-222 (decomposition);

5 nitro-furaldehyde N [4,6' bis (isopropylamino)- 1,3,5 triazinyl (2)] hydrazone, melting at 220- 222;

5 nitro furaldehyde N [4 methylamino 6 dimethylamino 1,3,5 triazinyl (2')] hydrazone, melting at 250-252 (decomposition);

5 nitro furaldehyde N [4 ethylarnino 6' isopropylamino 1,3,5' triazinyl (2)] hydrazone, melting at 199-201";

5 nitro furaldehyde N [4 methylamino 6 nbutylamino 1,3,5 triazinyl (2)] hydrazone, melting at 168-170;

5 nitro furaldehyde N [4,6 -bis(tert. butylamino) 1,3,5 triazinyl (2)] hydrazone, melting at 269-271 (decomposition);

5 nitro furaldehyde N [4,6' bis(allylamino)- l,3,5-triazinyl-(2)J-hydrazone, melting at 189190 (decomposition) 5 nitro furaldehyde N [4' amino 6 anilino- 1,3,5 -triazinyl- 2 -hydrazone;

5 nitro furaldehyde N [4 methylamino 6- anilino 1,3',5 triazinyl (2)] hydrazone;

5 nitro furaldehyde N [4 isopropylamino 6- anilino 1,3,5 triazinyl (2)] hydrazone;

5 nitro furaldehyde N [4' amino 6 (p chloroanilino) 1,3,5 triazinyl (2)] hydrazone;

5 nitro furaldehyde N [4 amino 6 (o chloroanilino) 1,3,5 triazinyl -(2')] hydrazone;

5 nitro furaldehyde N [4 amino 6 (o trifiuoromethylanilino) -1,3,5-triazinyl-(2 ]-hydrazone;

5 nitro furaldehyde N [4 amino 6 (p trifluoromethylanilino) 1,3',5 triazinyl (2)] hydrazone;

5 nitro furaldehyde N [4' amino 6 (o -to1ylamino) l,3,5 triazinyl (2)] hydrazone;

5 nitro furaldehyde N [4 amino- 6 (p tolyl amino) 1,3',5 triazinyl (2)] hydrazone;

5 nitro furaldehyde N [4 amino 6 (o-methoxyanilino) 1,3,5 triazinyl (2)] hydrazone;

5 nitro furaldehyde N [4 amino 6 (p methoxyanilino) 1,3,5 triazinyl (2)] hydrazone;

5 nitro furaldehyde N [4 amino 6 (p-ethoxyanilino) 1 ,3 ,5-triazinyl- (2) ]-hydrazone;

5 nitro furaldehyde N [4 amino 6 cyclohexylamino 1,3,5 triazinyl (2)] hydrazone;

5 nitro furaldehyde N [4 amino 6 cycloa pentylaminol ,3 ,5 -triazinyl- (2') ]-hydrazone;

5 nitro furaldehyde N [4 methylamino 6'- cyclopentylamino-1,3 ,5 -triazinyl- (2 J-hydrazone;

5 nitro furaldehyde N [4,6 bis(cyclohexylamino) 1,3,5 triazinyl (2)] hydrazone;

5 nitro furaldehyde N [4 amino 6 allylamino-1,3',5 -triazinyl- (2 -hydrazone;

5 nitro furaldehyde N [4 amino 6 -methallylamino-1',3,5-triazinyl-( 2 1 -hydrazone;

5 nitro furaldehyde N [4 amino 6 (2" hydroxyethylamino -1',3 ,5 -triazinyl- (2) -hydrazone;

5 nitro furaldehyde N [4,6 bis(2 hydroxyethylarnino) -1,3,5triazinyl-(2) ]-hydrazone;

5 nitro furaldehyde N [4 amino 6' (1" pyrrolidinyl) l ,3 ,5-triazinyl- (2) J-hydrazone;

5 nitro furaldehyde N [4 amino 6 piperidino-1,3 ,5 -triazinyl (2 ]-hydrazone;

5 nitro -furaldehyde N [4,6 bis(piperidino) 1,3,5-triazinyl- (2) -hydrazone;

5 nitro turaldehyde N [4,6 bis(2 hydroxypropylamino -1,3,5 -triazinyl- (2) -hydrazone;

5 nitro furaldehyde N [4 amino- 6' benzylamino- 1 ,3 ,5 -triazinyl- (2) -hydrazone, and

5 nitro furaldehyde N [4 amino 6 (p chlorobenzylamino) l ,3,5-triazinyl- (2 -hydrazone.

Example 6 A mixture of 3.2 g. of 2-hydrazino-4,6-bis[di-(2'-hydroxyethyl)-amino]-1,3,5-triazine, 16 ml. of ethanol and 1.4 g. of -nitro-2-furaldehyde is boiled under reflux for 1 hour. The solution is then cooled and the yellow solid product is collected. After recrystallisation from methanol, 5-nitro-2-furaldehyde-N'- [4,6-bis- [di- (2"-hydroxyethyl)-amino]-1',3',5'-triazinyl-(2')]-hydrazone is obtained which melts at 190192 with decomposition and contains water of crystallisation.

The 2-hydrazino-4,6-bis-[di-(2'-hydroxyethyl)-arnino]- 1,3,5-triazine may be prepared as follows:

A mixture of 6.4 g. of 2-chloro-4,6-bis-[di-(2-hydroxyethyl)-an1ino]-l,3,5-triazine, 24 ml. of ethyl alcohol and 3.0 g. of 100% hydrazine hydrate is boiled under reflux for 2 hours. The solution is concentrated by distillation and ml. of ethanol are distilled off. To the cooled residue 1 0 ml. of water are added and the solution is extracted with two portions of ml. of chloroform. A crystalline solid is deposited in the aqueous layer and is collected by filtration. Thus is obtained 2-hydrazino- 4,6-bis-[di(2-hydroxyethyl) amino]-l,3,5-triazine which melts at l32134 after recrystallisation from ethanol.

Similarly can be prepared S-nitro-2-furaldehyde-N- [4,6' bis (diethylamino) 1',3',5 triazinyl (2')]- hydrazone, melting at 111112.

Example 7 A mixture of 33.5 g. of 2-hydrazino-4-allylamino-6- isopropylamino-1,3,5-triazine and 21.0 g. of 5-nitro-2- furaldehyde in 118 ml. of ethanol is boiled under reflux for 30 minutes. On completion of the reaction 120 ml. of water are added and the mixture is cooled in ice. The yellow solid is collected on a filter and washed with aqueous ethanol. 5-nitro-2-furaldehyde-N'-[4 allylamino-6'-isopropylamino-l,3',5-triazinyl-(2')]-hydrazone melting at 201-202 with decomposition is so obtained as both red and yellow crystals after recrystallisation from ethanol.

The 2-hydrazino-4-allylamino-6-isopropylarnino 1,3,5- triazine may be prepared as follows:

A mixture of 4.6 g. of 2-chloro-4-al1ylamino-6-isopropylamino-l,3,5-triazine, 3 g. of 100% hydrazine hydrate, and 32 ml. of ethanol are boiled under reflux for 2 hours. 16 ml. of ethanol are then removed by distillation and to the residue 20 ml. of water are added. The aqueous residue is extracted with ml. of chloroform in two equal portions. The chloroform layer is washed with water and dried with anhydrous sodium sulphate. Evaporation of the chloroform gives crude 2-hydrazino-4-allylamino-6-isopropylamino-1,3,5-triazine melting indistinctly at 50-60". The crude hydrazine is converted directly to the hydrazone.

Similarly can be prepared:

5 nitro furaldehyde N [4-methylamino-6-(l"- methylheptylamino) 1',3',5 triazinyl-(Z)]-hyclrazone, melting at 153-155";

5 nitro furaldehyde N [4-methylamino-6-( 1"- methylpropylamino) l,3',5 triazinyl-(Z)J-hydrazone with double melting point at 143l47 and then at 167- 170;

5-nitro-furaldehyde N [4'-(2-hydroxyethylamino)- 6'-isopropylamino-1',3,5-triazinyl- (2) ]-hydrazone;

S-nitro-furaldchyde N' [4'-(2-methoxyethylamino)- 6-isopropylamino-1,3',5'-triazinyl- (2) ]-hydrazone;

5-nitro-furaldehyde-N-[4(3" methoxypropylamino)- 6'-isopropylamino-1',3',5-triazinyl-(2') ]-hydrazone;

5-nitro-furaldehyde-N'-[4'-(sec. butylamino)-6-isopropylamino-1',3',5 '-triazinyl-(2') ]-hydrazone, and

S-nItrO'furaIdehyde-N [4'-methallylamino 6 isopropylamino- 1 ',3 ,5 -triazinyl- (2') -hydrazone.

Example 8 14 g. of 2-hydrazino-4,6-diamino-1,3,5-triazine are dissolved in 225 ml. of water at 100, and 59 ml. of ethanol are added. To this solution at is added dropwise a solution of 21 g. of S-nitro-Z-furaldehyde in 59 m1. of ethanol over a period of 15 minutes. On completion of the addition, the reaction liquor is allowed to cool and the dark red product is collected on a filter. After recrystallisation from aqueous methanol this product yields S-nitro 2 furaldehyde-N[4',6'-diamino-1',3,5'-triazinyl(2')]-hydrazone which chars above 250.

The 2-hydrazino-4,6-diamino-1,3,5-triazine may be prepared as follows:

A mixture of 7.2 g. of 2-chloro-4,6-diamino-1,3,5-triazine, 118 ml. of ethanol and 7.5 g. of 100% hydrazine hydrate is boiled under reflux for 2 hours with stirring. The solution is concentrated by distillation and 66 ml. of ethanol are removed. To the hot residue ml. of water are added and this solution is stirred for 15 minutes, before being cooled and allowed to stand overnight. The white product is collected on a filter and is washed with aqueous ethanol. This product after recrystallisation from water yields 2-hydrazino-4,6-diamino-1,3,5-triazinc which melts at 27l275 with decomposition.

Similarly can be prepared:

5-nitro-furaldehydc-N-[4-amino 6' methylamino-l, 3',5-triazinyl-(2')]-hydrazone, charring at ca. 240250, and

5-nitro-furaldehyde-N'-[4-amino 6' dimethylamino- 1',3',5-triazinyl-(2)]-hydrazone, melting at 267-269 (decomposition).

Example 9 A mixture of 14.4 g. of 2-hydrazino-4-ethylamino-6- (3-methoxypropylamino)-1,3,5-triazine, 8.4 g. of S-nitro- 2-furaldehyde, and 47 ml. of ethanol is boiled under reflux for one hour. After cooling, a mixture of 19.5 ml. of 2 N sulphuric acid in 35 m1. of water is added to the liquor. Brown product separates and is collected on a filter. After recrystallisation from aqueous methanol, and charcoal treatment, this product yields 5-nitro-2- furaldehyde-N-[4'-ethylamino 6' (3"-methoxypropylamino)-1,3,5-triazinyl-(2)]-hydrazone sulphate which melts at 179-182 and contains water of crystallisation.

The 2-hydrazino-4-ethylamino 6 (3-methoxypropy1- amino)-1,3,5-triazine may be prepared as follows:

A mixture of 4.9 g. of 2-chloro-4-ethylamino-6-(3- methoxypropylamino)-1,3,5-triazine, 32 ml. of ethanol and 3 g. of hydrazine hydrate is boiled under reflux for /2 hour. The solution is concentrated by distillation and 22 ml. of ethanol are removed. To the cold residue 20 ml. of water are added and the solution is extracted with 3 portions of 30 m1. of chloroform. The combined chloroform extract is washed with 10 ml. of water, dried with anhydrous sodium sulphate, and evaporated to give a waxy solid product. This product is recrystallised from nitroethane, with charcoal treatment, to give Z-hydrazino- 4-ethylamino-6-(3'-methoxypropylarnino) 1,3,5 triazine which melts at 8688.

Similarly can be prepared 5-nitro-2-furaldehyde-N- [4 methylamino-6-n-propylamino-l,3,5-triazinyl-(2)]- hydrazone sulphate melting at 178-185 with decomposi- Example 10 A solution of 8.3 g. of furaldehyde-N-[4,6-bis-(dimethlyamino)-1',3,5'-triazinyl-(2)]-hydrazone in ml. of glacial acetic acid and 27 ml. of acetic anhydride is stirred at 10. To this solution is added a mixture of 4.1 g. of concentrated nitric acid, 11 ml. of acetic anhydride and 42 ml. of acetic acid dropwise over a period of 15 minutes. The liquor is stirred for 1 hour at 10-15" and is then poured into 1250 ml. of ice-water and neutralised with solid sodium bicarbonate. The yellow product which is precipitated is collected by filtration and washed with water. After recrystallisation from ethanol this product yields 5-nitro-2-furaldehyde-N-[4',6-bis(dimethylamino-1,3',5'-triazinyl-(2)]-hydrazone which melts at 201-203.

The furaldehyde-N-[4,6'-bis(dimethylamino)-1,3,5'- triazinyl-(Z) ]-hydrazone may be prepared as follows:

19.7 g. of 2-hydrazino-4,6-bis(dimethylamino)-1,3,5- triazine is dissolved in 263 ml. of boiling ethanol, and to this solution is added a solution of 9.6 g. of furaldehyde in 26 ml. of ethanol. The mixture is well stirred and is allowed to stand on a hot water bath for 1 hour. The almost white product which separates is collected by filtration of the cold reaction liquor and is washed with ethanol. After recrystallisation from methanol this product yields furaldehyde-N- [4,6-bis-(dimethylamino)-1', 3,5'-triazinyl-(2) ]-hydrazone which melts at 210-211.

Example 11 A solution of 12 g. of Z-hydrazino-4-amino 6-ethylamino-1,3,5-triazine in 50 ml. of water is prepared. To this solution 79 ml. of ethanol is added followed by a solution of 10 g. of 5-nitro-2-furaldehyde in 79 ml. of ethanol. The resulting mixture is boiled under reflux for 1 hour and then cooled. The 5-nitro-2-furaldehyde-N-[4-amino-6-ehylamino-1',3,5-triazinyl- (2 -hydrazone which separates is collected by filtration and washed with hot ethanol. The product so obtained has a melting point of 244-246 with decomposition.

The 2 hydrazino-4-amino-6-ethylamino-1,3,5-triazine may be prepared as follows:

A mixture of 5.2 g. of 2-chloro-4-amino-6-ethylamino- 1,3,5-triazine, 4.5 g. of 100% hydrazine hydrate and 55 ml. of ethanol is boiled under reflux for 1 /2 hours. The solution is cooled and the product which separates is removed by filtration and Washed with cold water until free of chloride ions. The product is recrystallised from water to give pure 2-hydrazino-4-amino-6-ethylamino-1,3,5-triazine melting at 133136 with decomposition.

Example 12 6 g. of S-nitrO-Z-furaldehyde-N[4,6-dichloro-1,3,5- triazinyl-(2)]-hydrazone is suspended in 28 ml. of dimethyl sulphoxide. To this suspension is cautiously added 8.8 g. of diethylamine with shaking. The mixture is heated on a boiling water bath for /2 hour, cooled and then poured into 106 ml. of 2 N sulphuric acid. The yellow precipitate which is formed is removed by filtration and washed with water. The precipitate is then suspended in 75 ml. of water and treated with 2 N sodium bicarbonate solution until the liquor is alkaline. The yellow suspension so formed is filtered and the residue in the filter is washed well with water. After recrystallisation from aqueous methanol and petroleum ether (boiling range 6080) this product yields yellow crystals of 5 nitro-2-furaldehyde-N-[4,6-bis-(diethylamino)-l,3, 5-triazinyl-(2)]-hydrazone melting at 11 1-1-12, identical with the product prepared as described in Example 6.

The 5 nitro-2-furaldehyde-N-[4,6-dichloro-1,35- triazinyl-(2) ]-hydrazone may be prepared as follows:

A solution of 6.2 g. of cyanuric chloride in 52 ml. of dioxane is prepared and to this vigorously stirred solution is added simultaneously a solution of 5.2 g. of 5- nitro-2-furaldehyde hydrazone in 155 ml. of dioxane at about 30 and a solution of 2.8 g. of sodium bicarbonate in 50 ml. of water. The addition of solutions takes 15 minutes. The mixture is stirred for a further 2 hours, and the product is then removed by filtration and washed with aqueous dioxane. After recrystallisation from nitroethane this product yields lemon yellow crystals of 5- nitro 2-furaldehyde-N-[4,6-dich1oro-l,3,5-triazinyl- (2) ]-hydrazone which does not melt below 300".

10.7 g. of cyanuric bromide can be used instead of 6.2 gl of cyanuric chloride.

What is claimed is:

1. A hydrazone of S-nitro-furaldehyde selected from 10 the class consisting of a free base and its non-toxic addition salts, said free base having the formula:

in which each of R and R independently, is a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, hydroxy-lower alkyl, lower alkoxylower alkyl, cyclohexyl, phenyl, halogenophenyl, trifluoromethylphenyl, lower alkylphenyl, lower alkoxyphenyl, phenyl-lower alkyl, halogenophenyl-lower alkyl, trifluoromethylphenyl-lower alkyl, lower alkylphenyl-lower alkyl, lower alkoxyphenyl-lower alkyl; each of R and R independently, is a member selected from the group consisting of hydrogen, lower alkyl and hydroxy-lower alkyl, and NR R as well as NR R can each be a member selected from the group consisting of l-pyrrolidinyl, piperidino, hexamethyleneimino and morpholino.

2. 5 nitro furaldehyde N [4 ethylamino 6- diethylamino-1,3',5-triazinyl-(2) ]-hydrazone.

3. 5 nitro furaldehyde N [4 isopropylamino- 6'-diethylamino-1',3,5-triazinyl-(2) J-hydrazone.

4. 5 nitro furaldehyde N [4,6 bis (ethylamino) -1',3,5-triazinyl-(2 ]-hydrazone.

5. 5 nitro furaldehyde N [4,6 bis (isopropylamino) -1',3 ,5 -triazinyl- 2) ]-hydrazone.

6. 5 nitro furaldehyde N [4 methylamino -6- isopropylamino-1,3 ,5 -triazinyl- (2) -hydrazone.

7. 5 nitro furaldehyde N [4 ethylamino 6'- isopropylamino-1',3 ,5 -triazinyl- 2) ]-hydrazone.

8. 5 nitro furaldehyde N [4 allylamino 6- isopropylamino-1,3 ,5-triazinyl- (2) ]-hydrazone.

9. 5 nitro furaldehyde N [4 methylamino 6'- sec. butyla1nino-1,3,5 -triazinyl-(2) -hydrazone.

10. 5 nitro furaldehyde N [4 ethylamino 6- methoxy propyl amino) 1,3,5 triazinyl (2) hydrazone sulphate.

11. 5 nitro furaldehyde N [4 amino 6 isopropylamino- 1 ,3,5-triazinyl- (2) -hydrazone.

12. 5 nitro 2 furaldehyde N [4,6' bis (isopropylamino -1,3 ,5 -triazinyl- (2) ]-hydrazone.

13. 5 nitro furaldehyde N [4,6 bis (tert. butylamino) l,3,5-triazinyl-(2) ]-hydrazone.

14. A hydrazone of S-nitro-furaldehyde of the formula:

Hal

1 OzNl fl-CH=NNH \\N o Hal wherein Hal is a member selected from the group consisting of chlorine and bromine.

15. 5 nitro furaldehyde N [4,6 dichloro 1,3, 5 -triazinyl- (2) ]-hydrazone.

References Cited in the file of this patent UNITED STATES PATENTS DAlelio et al Apr. 1, 1947 Sherman Sept. 20, 1960 OTHER REFERENCES 

1. A HYDRAZONE OF 5-NITRO-FURALDEHYDE SELECTED FROM THE CLASS CONSISTING OF A FREE BASE AND ITS NON-TOXIC ADDITION SALTS, SAID FREE BASE HAVING THE FORMULA: 